The pathogenesis of the uremic manifestations is not known and has been attributed to uremic toxin(s). No toxin has, as yet, been proven to cause some or all of the uremic abnormalities. We have accumulated evidence during the last three years suggesting that the excess levels of parathyroid hormone (PTH) in the blood of uremic patients may play an important role in the genesis of the uremic syndrome and that PTH may be a major uremic toxin. The specific aims of our research are to: 1. Examine the effect of PTH on in vitro systems to understand the mechanisms of action of the hormone on various organs and to explore whether such effects have relevance to any of the uremic manifestations. 2. Investigate the role of excess PTH in the genesis of the various components of the uremic syndrome in experimental animals with chronic renal failure and examine whenever feasible the effect of PTH on the function of various organs in animals with normal renal function. 3. Evaluate in renal failure patients the consequences of the prevention of secondary hyperparathyroidism as renal failure progresses (patients with moderate renal failure) and of the management of hyperparathyroidism (in patients with advanced renal failure) on the uremic syndrome. Our proposed research not only attempts to document a uremic toxin, but also to identify a toxin (PTH) whose source could be controlled, allowing us to prevent its accumulation and to reduce its levels if they are already elevated. Thus, our results may have tremendous clinical implications. They may provide rational approaches to ameliorate or prevent many of the components of the uremic syndrome.